1. Field of the Invention
The present invention relates to dihydrocaffeic acid derivatives and use as medicines thereof. More specifi cally, it relates to dihydrocaffeic acid derivatives having the ability to induce the production and secretion of nerve growth factor (hereinafter abbreviated as "NGF") in the local tissue of the brain, and to prophylactic and therapeutic preparations for regressive disorders of the central nervous system containing these derivatives as active ingredients.
2. Description of the Related Art
Researches have been advanced rapidly in order to establish early diagnosis and etiological therapy for various kinds of senile diseases along with the increasing average span of life in the world. Regressive disorders of the central nervous system are also the principal subjects of researches. In particular, senile dementia of Alzheimer type (hereinafter abbreviated as "SDAT") is getting a serious social problem in that SDAT noticeably increases primarily in advanced countries and in that SDAT is progressive and takes a tragic course. Particularly in recent years, many researchers and clinicians have extensively investigated SDAT, but neither fundamental elucidation of the disease nor effective early diagnosis and therapy have been established.
However, according to many accumulated pathological findings, it has been clarified that direct causes of the decline of memory and disorientation which are characteristic early symptoms of SDAT are the progressive degeneration of magnocellular cholinergic tracts and the insufficiency of its responsible region, the aforesaid cholinergic tracts being projected from the basal forebrain into the cerebral cortex and hippocampus which are the centers of memory and learning. In fact, there is the report that the symptoms of SDAT have been slightly relieved by administering, to SDAT patients, a precursor in acetylcholine biosynthesis or an inhibitor of choline esterase as an activation treatment for the brain cholinergic neuron. However, the results are not considered to be as effective as expected.
NGF has been researched widely since it was discovered by R. Levi-Monterlcini, S. Cohen et al., and it has already been certified by some physiological experiments that NGF is the essential factor for the peripheral nervous system relating to differentiation and growth of sensory and sympathetic nerves of a fetus and relating to the survival and maintenance of functions of the sympathetic neurons of an adult.
NGF is a biologically active substance which is present in ultra trace amounts, and therefore in spite of researches for a long period of time, any precise information has not been obtained which is concerned with the distribution and movement of NGF in the tissue for directly supporting the vital functions thereof. Most recently, a highly sensitive enzyme-linked immunosorbent assay (hereinafter abbreviated as ELISA) to identify the active subunit of NGF, i.e., .beta.-NGF (hereinafter simply referred to as "NGF") has been developed and improved, so that detection-sensitivity and specificity suitable for the above-mentioned examination have been attained [S. Furukawa et al., J. Neurochem., 40, 734-744 (1983); S. Korshing and H. Thoenen, Proc. Natl. Acad. Sci. USA, 80, 3513-3516 (1983)].
Furthermore, the NGF gene has been cloned and its structure has been analyzed, and a method for determining messenger RNA (hereinafter abbreviated as "mRNA") of .beta.-NGF has been also established which makes use of complemental DNA (hereinafter abbreviated as "cDNA") as a probe [D. L. Shelton and L. F. Reichardt, Proc. Natl. Acad. Sci. USA, 81, 7951-7955 (1984); and R. Heumann et al., EMBO J., 3, 3183-3189 (1984)].
The utilization of this technique has demonstrated that a positive correlation is present between the degree of sympathetic innervation in the peripheral nervous system and the gene expression of NGF in the innervated tissue.
More surprisingly, NGF has also been detected in the central nervous system of rates, particularly in hippocampus, neocortex, basal forebrain, e.g., septum, olfactory bulb, diagonal band of Broca and nucleus basal magnocellularis. In addition, it has been apparent that the mRNA content of NGF is high in the hippocampus and neocortex, but the content thereof in the septum of the basal forebrain is as low as in other regions of the brain in which no NGF is detected [S. Korshing et al., EMBO J., 4, 1389-1393 (1985)]. Afterward, the results of the experiments have been successively traced by other research groups [D. L. Shelton and L. F. Reichardt, Proc. Natl. Acad. Sci. USA, 83, 2714-2718 (1986); S. R. Whittemore et al., Proc. Natl. Acad. Sci. USA, 83, 817-821 (1986)].
According to these results, the NGF gene is expressed not only in the peripheral nervous system but also in the central nervous system, and moreover it has been elucidated that NGF is produced and secreted in the innervating regions of the cholinergic tracts projecting from the origins of the basal forebrain to the neocortex and hippocampus, i.e., the centers of memory and learning, and it is then taken up at the nerve endings and transported in a retrograde manner through axons to reach somata in the origins. It has been already certified by a series of physiological experiments that NGF is the essential factor for the survival and the maintenance of functions in the cholinergic tracts. Thus, these results have demonstrated that NGF specifically functions as a "neurotropic factor" also in the central nervous system.
Afterward, these experiments have been traced by some research groups and have also been supported by investigations regarding NGF receptors and their distribution in the brain.
In the course of the researches on the function of NGF as the neurotropic factor in the central nervous system, the present inventors have got to know that the disorders of memory and learning which are the early symptoms of SDAT are directly caused by the progressive degeneration of cholinergic tracts and the insufficiency of the responsible region which is brought about thereby, but the truly fundamental cause of the disorders is the insufficiency of the production and secretion of NGF in particular regions of the brain.
That is, the present inventors consider that a conventional symptomatic therapy against SDAT such as a supplementation therapy and/or an availability improvement therapy by the use of acetylcholine cannot provide remarkably good results, and that if the functionally vicious cycle between the responsible nerves and regions under their control can be cut off by maintaining the production and secretion of NGF in the cerebral cortex and hippocampus, more effective results can be obtained.
In this connection, the technique for mass production of human-type .beta.-NGF has already been achieved by the cloning of a gene, but the supplemental therapy of NGF itself which is a protein having a molecular weight of more than 10,000 is considerably limited from pharmacological and pharmaceutical viewpoints. In particular, the application of NGF to the central nervous system is far from realization at this point of time.
In view of the foregoing, it is important to search a low-molecular weight compound having the ability to induce the production and secretion of NGF in the particular tissue so as to establish the substantial and effective supplemental NGF therapy. The present inventors have already reported catechol derivatives having such a function (Ikeda: Japanese Patent Laid-open No. 63-83020 and Japanese Patent Application No. 63-63516). Furthermore, there are also reports from Furukawa et al. [Y. Furukawa et al., J. Boil. Chem., 261, 6039 (1986) and FEBS Letters, 208, 258 (1986)]. These reported compounds are excellent in the production and secretion of NGF, but their absorbency in the case of oral administration and their concentration retention in blood are not sufficient.